RADIOPHARMACY GMP QC HPLC VALIDATION

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RADIOPHARMACY GMP

QC HPLC VALIDATION

AERTS Joël PhD, PARIS-DIDEROT, ULG

GIACOMELLI Fabrice PhD, ULG

HUBERT Philippe PhD, ULG

IANNIELLO Jimmy Pharm, ULG

MARINI Roland PhD, ULG

17th symposium of the Belgian Society of Nuclear Medicine 9 - 10 May 2015, Maastricht, The Netherlands

GMP

QC HPLC VALIDATION

EudraLex - Volume 4 GMP Guidelines

Good Manufacturing Practice is that part of Quality Management which ensures that products are

consistently produced and controlled to the quality standards appropriate to their intended use and as required by the Marketing Authorisation, Clinical Trial Authorisation or product specification.

Good Manufacturing Practice is concerned with both production and quality control.

EudraLex - Volume 4 GMP Guidelines

Quality Control is that part of Good Manufacturing Practice

which is concerned with sampling, specifications and testing, and with the organisation, documentation and release procedures which ensure that the necessary and relevant tests are actually carried out and that materials are not released for use, nor products released for sale or supply, until their quality has been judged to be satisfactory.

ISO/IEC 17025:2005 5.4.5

Validation is the confirmation by

examination and the provision of objective evidences that the particular requirements for a specific intended use are fulfilled.

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GMP

PRODUCTION

Finished Product Raw Material FACILITIES OPERATORS Methods

QUALITY CONTROL

SAMPLES RESULTS FACILITIES OPERATORS Methods SAMPLING VALIDATION concerns METHODS QUALIFICATION concerns FACILITIES & OPERATORS

Some references

• ISO/IEC 17025 General requirements for the competence of testing

and calibration laboratories

• ISO 5725 Accuracy (trueness and precision) of measurement

methods and results

• ICH Q2 Validation of Analytical procedures

Q2A: terminology ; Q2B: methodology

• Directive 96/23/CE and decision 2002/657/CE

• EDQM Technical Guide for the elaboration of monographs, 2011

• STP PHARMA PRATIQUES, 13, 3, 2003 Validation of quantitative

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Criteria (ISO 17025)

• Specificity

• Accuracy = trueness + precision Total error = bias + variance

• Precision • Repeatability

• Intermediate precision

• Limit of detection (LOD) and Limit of quantification (LOQ)

• Assay range

• Linearity (results vs conct.) <> response function (signal vs conct.)

Response function (calibration curve)

Concentration Concentration

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Criteria to be evaluated

Types of test

Criteria Identification Assay

Impurity Limit Test

Impurity Quantitation

Specificity YES YES YES YES

Accuracy YES YES

Repeatability YES YES

Intermediate precision YES YES

Limit of Detection LOD YES YES

Limit of Quantification LOQ YES

Linearity YES YES

Assay Range YES YES

Identification

3 important rules for the validation of

analytical methods

• Validation covers all operations of the methods from sampling (volume or weight) to generation of results (including

mathematical transformations of data).

• Validation covers a finite range of concentration: extrapolation outside the range is not allowed.

• Validation is matrix specific. A new validation must be performed for each new matrix.

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Validation of Eur. Pharm. methods ?

• The pharmacopoeial methods given in monographs and general chapters have been validated in accordance with accepted scientific practice and current recommendations on analytical validation. Unless otherwise stated in the monograph or general chapter, validation of the test methods by the analyst is not required.

• When implementing a pharmacopoeial method, the user must assess whether and to what extent the suitability of the method under the actual conditions of use needs to be demonstrated according to relevant monographs, general chapters and quality systems.

Accuracy profile as decision tool

STP PHARMA PRATIQUES, 13, 3, 2003 Validation of quantitative analytical procedure,

Harmonization of approaches, Hubert P. et al.

λ

= acceptance

limit

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19

_{F-FDG limit test in}

18

_F-FDG

• FLUDEOXYGLUCOSE (18_{F) INJECTION, European Pharmacopeia 8,}

01/2014:1325: MAX: 0.5 mg/V V= maximum injected volume

• Liquid chromatography

- Dionex ICS3000 with autosampler - Detection: amperometry (30°C)

- Colonne Dionex Carbopac PA10 (25°C) - 1mL/min 100mM NaOH

- Conditionnement: 1M NaOH every 3 injections

Criteria to be evaluated

EP01/2014:1325

Types of test

Accuracy YES YES

Linearity YES YES

Assay Range YES YES

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19

_{F-FDG limit test in}

18

_F-FDG

FDM 6.17 FDG 7.02 ClDG 7.62 System Suitability:

Minimum resolution for FDM / FDG = 1.5

Calculated: 1.6

Quantitation at low concentration

Types of test

Accuracy YES YES

Linearity YES YES

Assay Range YES YES

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PHASE 1 : organization

• Description of the analytical method

• Information on product to assay and analytical system (HPLC, GC…) • Protocols for samples preparation

• CS: calibration samples = solution of product in a suitable solvent • VS: validation samples = solution of product in the real matrix

• Concentration levels for CS et VS

• Validation plan. Ex. 3 days/1op or 2 days/2op

• Criteria to be evaluated

PHASE 2 : preparation of CS

Bulk 1 dilutions 1 Bulk 2 dilution 2 Bulk p dilution p SERIES (days)

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Example: preparation of CS for FDG

µg/mL 50 25 10 5 0.5 LOQ 19

_{F-FDG in water}

PHASE 3 : preparation of VS

Bulk dilutions Matrix Loading 50 25 10 5 µg/mL 19

_{F-FDG in matrix}

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Results of injections of series

Relationship between the introduced and the back-calculated amounts

Linear Regression Through 0 fitted with the level 0.5 only calibration curve

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19

_{F-FDG limit test in}

18

_F-FDG

• FLUDEOXYGLUCOSE (18_{F) INJECTION, European Pharmacopeia 8,}

01/2014:1325: MAX: 0.5 mg/V V= maximum injected volume

• Liquid chromatography

- Dionex ICS3000 with autosampler - Detection: amperometry (30°C)

- Colonne Dionex Carbopac PA10 (25°C) - 1mL/min 100mM NaOH

- Conditionnement: 1M NaOH every 3 injections

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